title: Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.
abstract: Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11β-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.
authors.affiliation: Institute of Applied Synthetic Chemistry, University of Technology, Getreidemarkt 9, 1060 Vienna, Austria.
authors.forename: Rawindra
authors.initials: R
authors.lastname: Gaware
authors.forename: Rupesh
authors.initials: R
authors.lastname: Khunt
authors.forename: Laszlo
authors.initials: L
authors.lastname: Czollner
authors.forename: Christian
authors.initials: C
authors.lastname: Stanetty
authors.forename: Thierry
authors.initials: T
authors.lastname: Da Cunha
authors.forename: Denise V
authors.initials: DV
authors.lastname: Kratschmar
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Paul
authors.initials: P
authors.lastname: Kosma
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jordis
authors.forename: Dirk
authors.initials: D
authors.lastname: Classen-Houben
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
chemical_list: C559073:2,3,4,5,5a,6,7,7a,7b,8,9,9a,10,11,12,13,13a,15,15a,15b-eicosahydro-5,5,7a,7b,9a,12,15b-heptamethyl-3,15-dioxo-N-hydroxy-N-methyl-1H-chryseno(2,1-c)azepine-12-carboxylic acid amide; D001381:Azepines; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D014508:Urea; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D006034:Glycyrrhetinic Acid